ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Reactions to articaine are characteristic of those associated with other amide-type local anesthetics. Adverse reactions to this group of drugs may also result from excessive plasma levels (which may be due to overdosage, unintentional intravascular injection, or slow metabolic degradation), injection technique, volume of injection, or hypersensitivity or they may be idiosyncratic.. The most common adverse reactions (incidence >2%) are headache and pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact DENTSPLY Pharmaceutical at 1-800-989-8826 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Studies Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The reported adverse reactions are derived from clinical trials in the United States and the United Kingdom. Table displays the adverse reactions reported in clinical trials where 882 individuals were exposed to ARTICADENT containing epinephrine 1:100,000. Table displays the adverse reactions reported in clinical trials where 182 individuals were exposed to ARTICADENT containing epinephrine 1:100,000 and 179 individuals were exposed to ARTICADENT containing epinephrine 1:200,000.. Adverse reactions observed in at least 1% of patients:Table 2: Adverse Reactions in Controlled Trials with an Incidence of 1% or Greater in Patients Administered ARTICADENT containing Epinephrine 1:100,000Body System/ReactionARTICADENT containing epinephrine1:100,000 (N=882) IncidenceBody as wholeFace Edema13 (1%)Headache31 (4%)Infection10 (1%)Pain114 (13%)Digestive systemGingivitis13 (1%)Nervous systemParesthesia11 (1%)Table 3: Adverse Reactions in Controlled Trials with an Incidence of 1% or Greater in Patients Administered ARTICADENT containing Epinephrine 1:200,000 and ARTICADENT containing Epinephrine 1:100,000ReactionARTICADENT with epinephrine 1:200,000 (N=179) IncidenceARTICADENT with epinephrine 1:100,000 (N=182) IncidenceAny adverse reaction33 (18%)35 (19%)Pain11 (6.1%)14 (7.6%)Headache9 (5%)6 (3.2%)Positive blood aspiration into syringe3 (1.6%)6 (3.2%)Swelling3 (1.6%)5 (2.7%)Trismus1 (0.5%)3 (1.6%)Nausea and emesis3 (1.6%)0 (0%)Sleepiness2 (1.1%)1 (0.5%)Numbness and tingling1 (0.5%)2 (1%)Palpitation0 (0%)2 (1%)Ear symptoms (earache, otitis media)1 (0.5%)2 (1%)Cough, persistent cough0 (0%)2 (1%). Adverse reactions observed in less than 1% of patients:Table 4: Adverse Reactions in Controlled Trials with an Incidence of less than 1% but Considered Clinically Relevant in Patients Administered ARTICADENTBody SystemReactionsBody as WholeAsthenia; back pain; injection site pain; burning sensation above injection site; malaise; neck painCardiovascular SystemHemorrhage; migraine; syncope; tachycardia; elevated blood pressureDigestive SystemDyspepsia; glossitis; gum hemorrhage; mouth ulceration; nausea; stomatitis; tongue edemas; tooth disorder; vomitingHemic and Lymphatic SystemEcchymosis; lymphadenopathyMetabolic and Nutritional SystemEdema; thirstMusculoskeletal SystemArthralgia; myalgia; osteomyelitisNervous SystemDizziness; dry mouth; facial paralysis; hyperesthesia; increased salivation; nervousness; neuropathy; paresthesia; somnolence; exacerbation of Kearns-Sayre SyndromeRespiratory SystemPharyngitis; rhinitis; sinus pain; sinus congestionSkin and AppendagesPruritus; skin disorderSpecial SensesEar pain; taste perversion. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of ARTICADENT. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Persistent paresthesias of the lips, tongue, and oral tissues have been reported with use of articaine hydrochloride, with slow, incomplete, or no recovery. These postmarketing events have been reported chiefly following nerve blocks in the mandible and have involved the trigeminal nerve and its branches.Hypoesthesia has been reported with use of articaine, especially in pediatric age groups, which is usually reversible. Prolonged numbness can result in soft tissue injuries such as that of the lips and tongue in these age groups.Ischemic injury and necrosis have been described following use of articaine with epinephrine and have been postulated to be due to vascular spasm of terminal arterial branches.Paralysis of ocular muscles has been reported, especially after posterior, superior alveolar injections of articaine during dental anesthesia. Symptoms include diplopia, mydriasis, ptosis, and difficulty in abduction of the affected eye. These symptoms have been described as developing immediately after injection of the anesthetic solution and persisting one minute to several hours, with generally complete recovery.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Articaine HCl is an amide local anesthetic. Local anesthetics block the generation and conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of the affected nerve fibers. Epinephrine is vasoconstrictor added to articaine HCl to slow absorption into the general circulation and thus prolong maintenance of an active tissue concentration.. 12.2 Pharmacodynamics. Clinically, the order of loss of nerve function is as follows: (1) pain; (2) temperature; (3) touch; (4) proprioception; and (5) skeletal muscle tone.The onset of anesthesia has been shown to be within to minutes of injection of ARTICADENT. Complete anesthesia lasts approximately hour for infiltrations and up to approximately hours for nerve block.Administration of ARTICADENT results in 3- to 5-fold increase in plasma epinephrine concentrations compared to baseline; however, in healthy adults it does not appear to be associated with marked increases in blood pressure or heart rate, except in the case of accidental intravascular injection [see Warnings and Precautions (5.1)]. 12.3 Pharmacokinetics. Absorption:Following dental injection by the submucosal route of an articaine solution containing epinephrine 1:200,000, articaine reaches peak blood concentration about 25 minutes after single dose injection and 48 minutes after three doses. Peak plasma levels of articaine achieved after 68 and 204 mg doses are 385 and 900 ng/mL, respectively.Following intraoral administration of near maximum dose of 476 mg, articaine reaches peak blood concentrations of 2037 and 2145 ng/mL for articaine solution containing epinephrine 1:100,000 and 1:200,000, respectively, approximately 22 minutes post-dose.. Distribution:Approximately 60 to 80% of articaine HCl is bound to human serum albumin and y-globulins at 37C in vitro. Elimination:. Metabolism: Articaine HCl is metabolized by plasma carboxyesterase to its primary metabolite, articainic acid, which is inactive. In vitro studies show that the human liver microsome P450 isoenzyme system metabolizes approximately 5% to 10% of available articaine with nearly quantitative conversion to articainic acid.. Excretion: At the dose of 476 mg of articaine, the elimination half-life was 43.8 minutes and 44.4 minutes for articaine solution containing epinephrine 1:100,000 and 1:200,000, respectively. Articaine is excreted primarily through urine with 53-57% of the administered dose eliminated in the first 24 hours following submucosal administration. Articainic acid is the primary metabolite in urine. minor metabolite, articainic acid glucuronide, is also excreted in urine. Articaine constitutes only 2% of the total dose excreted in urine.

CLINICAL STUDIES SECTION.

6.1 Clinical Studies Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The reported adverse reactions are derived from clinical trials in the United States and the United Kingdom. Table displays the adverse reactions reported in clinical trials where 882 individuals were exposed to ARTICADENT containing epinephrine 1:100,000. Table displays the adverse reactions reported in clinical trials where 182 individuals were exposed to ARTICADENT containing epinephrine 1:100,000 and 179 individuals were exposed to ARTICADENT containing epinephrine 1:200,000.. Adverse reactions observed in at least 1% of patients:Table 2: Adverse Reactions in Controlled Trials with an Incidence of 1% or Greater in Patients Administered ARTICADENT containing Epinephrine 1:100,000Body System/ReactionARTICADENT containing epinephrine1:100,000 (N=882) IncidenceBody as wholeFace Edema13 (1%)Headache31 (4%)Infection10 (1%)Pain114 (13%)Digestive systemGingivitis13 (1%)Nervous systemParesthesia11 (1%)Table 3: Adverse Reactions in Controlled Trials with an Incidence of 1% or Greater in Patients Administered ARTICADENT containing Epinephrine 1:200,000 and ARTICADENT containing Epinephrine 1:100,000ReactionARTICADENT with epinephrine 1:200,000 (N=179) IncidenceARTICADENT with epinephrine 1:100,000 (N=182) IncidenceAny adverse reaction33 (18%)35 (19%)Pain11 (6.1%)14 (7.6%)Headache9 (5%)6 (3.2%)Positive blood aspiration into syringe3 (1.6%)6 (3.2%)Swelling3 (1.6%)5 (2.7%)Trismus1 (0.5%)3 (1.6%)Nausea and emesis3 (1.6%)0 (0%)Sleepiness2 (1.1%)1 (0.5%)Numbness and tingling1 (0.5%)2 (1%)Palpitation0 (0%)2 (1%)Ear symptoms (earache, otitis media)1 (0.5%)2 (1%)Cough, persistent cough0 (0%)2 (1%). Adverse reactions observed in less than 1% of patients:Table 4: Adverse Reactions in Controlled Trials with an Incidence of less than 1% but Considered Clinically Relevant in Patients Administered ARTICADENTBody SystemReactionsBody as WholeAsthenia; back pain; injection site pain; burning sensation above injection site; malaise; neck painCardiovascular SystemHemorrhage; migraine; syncope; tachycardia; elevated blood pressureDigestive SystemDyspepsia; glossitis; gum hemorrhage; mouth ulceration; nausea; stomatitis; tongue edemas; tooth disorder; vomitingHemic and Lymphatic SystemEcchymosis; lymphadenopathyMetabolic and Nutritional SystemEdema; thirstMusculoskeletal SystemArthralgia; myalgia; osteomyelitisNervous SystemDizziness; dry mouth; facial paralysis; hyperesthesia; increased salivation; nervousness; neuropathy; paresthesia; somnolence; exacerbation of Kearns-Sayre SyndromeRespiratory SystemPharyngitis; rhinitis; sinus pain; sinus congestionSkin and AppendagesPruritus; skin disorderSpecial SensesEar pain; taste perversion.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For dental procedures by intraoral submucosal infiltration or nerve block. (2.1)-For infiltration: 0.5-2.5 mL (20-100 mg articaine HCl)-For nerve block: 0.5-3.4 mL (20-136 mg articaine HCl)-For oral surgery: 1.0-5.1 mL (40-204 mg articaine HCl) For most routine dental procedures, ARTICADENT containing epinephrine 1:200,000 is preferred. However, when more pronounced hemostasis or improved visualization of the surgical field are required, ARTICADENT containing epinephrine 1:100,000 may be used. (2.1)Maximum recommended dosages (2.2):-Healthy adults: mg/kg of articaine HCl and 0.0017 mg/kg of epinephrine (equivalent to 0.175 mL/kg for either product presentation, articaine HCl and epinephrine 1:100,000 or 1:200,000)-Pediatric patients: 4-16 years: mg/kg of articaine HCl and 0.0017 mg/kg of epinephrine (equivalent to 0.175 mL/kg for either product presentation, articaine HCl and epinephrine 1:100,000 or 1:200,000) For dental procedures by intraoral submucosal infiltration or nerve block. (2.1)-For infiltration: 0.5-2.5 mL (20-100 mg articaine HCl)-For nerve block: 0.5-3.4 mL (20-136 mg articaine HCl)-For oral surgery: 1.0-5.1 mL (40-204 mg articaine HCl) -For infiltration: 0.5-2.5 mL (20-100 mg articaine HCl). -For nerve block: 0.5-3.4 mL (20-136 mg articaine HCl). -For oral surgery: 1.0-5.1 mL (40-204 mg articaine HCl). For most routine dental procedures, ARTICADENT containing epinephrine 1:200,000 is preferred. However, when more pronounced hemostasis or improved visualization of the surgical field are required, ARTICADENT containing epinephrine 1:100,000 may be used. (2.1). Maximum recommended dosages (2.2):-Healthy adults: mg/kg of articaine HCl and 0.0017 mg/kg of epinephrine (equivalent to 0.175 mL/kg for either product presentation, articaine HCl and epinephrine 1:100,000 or 1:200,000)-Pediatric patients: 4-16 years: mg/kg of articaine HCl and 0.0017 mg/kg of epinephrine (equivalent to 0.175 mL/kg for either product presentation, articaine HCl and epinephrine 1:100,000 or 1:200,000) -Healthy adults: mg/kg of articaine HCl and 0.0017 mg/kg of epinephrine (equivalent to 0.175 mL/kg for either product presentation, articaine HCl and epinephrine 1:100,000 or 1:200,000). -Pediatric patients: 4-16 years: mg/kg of articaine HCl and 0.0017 mg/kg of epinephrine (equivalent to 0.175 mL/kg for either product presentation, articaine HCl and epinephrine 1:100,000 or 1:200,000). 2.1 Important Dosage Information. Table summarizes the recommended dosages of ARTICADENT administered by intraoral submucosal infiltration or nerve block for various types of anesthetic dental procedures in healthy adults and pediatric patients.Table 1: Recommended Dosages for Both StrengthsProcedureARTICADENT InjectionVolume (mL)Total dose of articaine HCl (mg)Infiltration0.5 mL to 2.5 mL20 mg to 100 mgNerve block0.5 mL to 3.4 mL20 mg to 136 mgOral surgery1 mL to 5.1 mL40 mg to 204 mgThe recommended dosages of ARTICADENT in healthy adults serve only as guide to the amount of anesthetic required for most routine dental procedures. The dosages to be used in adults depend on several factors such as type and extent of surgical procedure, depth of anesthesia, degree of muscular relaxation, and condition of the patient. In all cases, administer the lowest dosage that will produce the desired result.The dosages of ARTICADENT to be used in pediatric patients aged to 16 years old are determined by the age and weight of the patient and the type of dental procedure. For most routine dental procedures, ARTICADENT containing epinephrine 1:200,000 is preferred. However, when more pronounced hemostasis or improved visualization of the surgical field are required, ARTICADENT containing epinephrine 1:100,000 may be used.The onset of anesthesia and the duration of anesthesia are proportional to the dosage of the local anesthetic used. Exercise caution when employing large volumes because the incidence of adverse reactions may be dose-related.. 2.2 Maximum Recommended Dosages. Healthy Adults: The maximum recommended dosage of ARTICADENT is mg/kg of articaine and 0.0017 mg/kg of epinephrine (equivalent to 0.175 mL/kg for either product presentation, articaine HCl and 1:100,000 or 1:200,000 epinephrine).Pediatric Patients Ages to 16 Years: The maximum recommended dosage of ARTICADENT is mg/kg of articaine and 0.0017 mg/kg of epinephrine (equivalent to 0.175 mL/kg for either product presentation, articaine HCl and 1:100,000 or 1:200,000 epinephrine) [see Use in Specific Populations (8.4)].. Healthy Adults: The maximum recommended dosage of ARTICADENT is mg/kg of articaine and 0.0017 mg/kg of epinephrine (equivalent to 0.175 mL/kg for either product presentation, articaine HCl and 1:100,000 or 1:200,000 epinephrine).. Pediatric Patients Ages to 16 Years: The maximum recommended dosage of ARTICADENT is mg/kg of articaine and 0.0017 mg/kg of epinephrine (equivalent to 0.175 mL/kg for either product presentation, articaine HCl and 1:100,000 or 1:200,000 epinephrine) [see Use in Specific Populations (8.4)].. 2.3 Dosage in Specific Populations. Lower dosages or dosage reduction may be required in debilitated patients, acutely ill patients, elderly patients, and pediatric patients commensurate with their age and physical condition. No studies have been performed in patients with renal or liver impairment. Exercise caution when using ARTICADENT in patients with severe liver disease. [see Warnings and Precautions (5.2), Use in Specific Populations (8.4, 8.5, and 8.6)]. 2.4 Important Administration Instructions. Visually inspect ARTICADENT for particulate matter and discoloration prior to administration.Prior to using the glass cartridges, disinfect by wiping the cap thoroughly with USP grade isopropyl alcohol (70%). Avoid use of isopropyl alcohol, as well as solutions of ethyl alcohol that are not of USP grade because they may contain denaturants that are injurious to rubber. Immersion is not recommended. Discard unused portion.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection (clear, colorless solution), provided in:Glass cartridges (single-dose) containing (less than full cartridge or more than one cartridge may be used for an individual patient):-Articaine hydrochloride 4% (40 mg/mL) and epinephrine 1:200,000 (as epinephrine bitartrate 0.009 mg/mL)-Articaine hydrochloride 4% (40 mg/mL) and epinephrine 1:100,000 (as epinephrine bitartrate 0.018 mg/mL) Glass cartridges (single-dose) containing (less than full cartridge or more than one cartridge may be used for an individual patient):-Articaine hydrochloride 4% (40 mg/mL) and epinephrine 1:200,000 (as epinephrine bitartrate 0.009 mg/mL)-Articaine hydrochloride 4% (40 mg/mL) and epinephrine 1:100,000 (as epinephrine bitartrate 0.018 mg/mL) -Articaine hydrochloride 4% (40 mg/mL) and epinephrine 1:200,000 (as epinephrine bitartrate 0.009 mg/mL). -Articaine hydrochloride 4% (40 mg/mL) and epinephrine 1:100,000 (as epinephrine bitartrate 0.018 mg/mL). Injection provided in:Glass cartridges (single-dose) containing:-Articaine hydrochloride 4% (40 mg/mL) and epinephrine 1:200,000 (as epinephrine bitartrate 0.009 mg/mL) (3)-Articaine hydrochloride 4% (40 mg/mL) and epinephrine 1:100,000 (as epinephrine bitartrate 0.018 mg/mL) (3) Glass cartridges (single-dose) containing:-Articaine hydrochloride 4% (40 mg/mL) and epinephrine 1:200,000 (as epinephrine bitartrate 0.009 mg/mL) (3)-Articaine hydrochloride 4% (40 mg/mL) and epinephrine 1:100,000 (as epinephrine bitartrate 0.018 mg/mL) (3) -Articaine hydrochloride 4% (40 mg/mL) and epinephrine 1:200,000 (as epinephrine bitartrate 0.009 mg/mL) (3). -Articaine hydrochloride 4% (40 mg/mL) and epinephrine 1:100,000 (as epinephrine bitartrate 0.018 mg/mL) (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. The administration of local anesthetic solutions containing epinephrine to patients receiving monoamine oxidase inhibitors, nonselective beta-adrenergic antagonists, or tricyclic antidepressants may produce severe, prolonged hypertension. Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine. Concurrent use of these agents should be avoided; however, in situations when concurrent therapy is necessary, careful patient monitoring is essential [see Warnings and Precautions (5.2)]. Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics:Table 5: Examples of Drugs Associated with MethemoglobinemiaClassExamplesNitrates/Nitritesnitric oxide, nitroglycerin, nitroprusside, nitrous oxideLocal anestheticsarticaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaineAntineoplastic agentscyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicaseAntibioticsdapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamidesAntimalarialschloroquine, primaquineAnticonvulsantsphenobarbital, phenytoin, sodium valproateOther drugsacetaminophen, metoclopramide, quinine, sulfasalazine. Monoamine Oxidase Inhibitors, Nonselective Beta-Adrenergic Antagonists, or Tricyclic Antidepressants: May produce severe, prolonged hypertension (7)Phenothiazines and Butyrophenones: May reduce or reverse the pressor effect of epinephrine (7).

OVERDOSAGE SECTION.

10 OVERDOSAGE. Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics or to unintended subarachnoid injection of local anesthetic solution [see Warnings and Precautions (5.1, 5.2)]. The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patients state of consciousness after each local anesthetic injection. At the first sign of change, oxygen should be administered.The first step in the management of convulsions, as well as hypo-ventilation, consists of immediate attention to the maintenance of patent airway and assisted or controlled ventilation as needed. The adequacy of the circulation should be assessed. Should convulsions persist despite adequate respiratory support, treatment with appropriate anticonvulsant therapy is indicated. The practitioner should be familiar with the use of anticonvulsant drugs, prior to the use of local anesthetics. Supportive treatment of circulatory depression may require administration of intravenous fluids and, when appropriate, vasopressor.If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmias, and/or cardiac arrest. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted.For additional information about overdose treatment, call poison control center (1-800-222-1222).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption:Following dental injection by the submucosal route of an articaine solution containing epinephrine 1:200,000, articaine reaches peak blood concentration about 25 minutes after single dose injection and 48 minutes after three doses. Peak plasma levels of articaine achieved after 68 and 204 mg doses are 385 and 900 ng/mL, respectively.Following intraoral administration of near maximum dose of 476 mg, articaine reaches peak blood concentrations of 2037 and 2145 ng/mL for articaine solution containing epinephrine 1:100,000 and 1:200,000, respectively, approximately 22 minutes post-dose.. Distribution:Approximately 60 to 80% of articaine HCl is bound to human serum albumin and y-globulins at 37C in vitro. Elimination:. Metabolism: Articaine HCl is metabolized by plasma carboxyesterase to its primary metabolite, articainic acid, which is inactive. In vitro studies show that the human liver microsome P450 isoenzyme system metabolizes approximately 5% to 10% of available articaine with nearly quantitative conversion to articainic acid.. Excretion: At the dose of 476 mg of articaine, the elimination half-life was 43.8 minutes and 44.4 minutes for articaine solution containing epinephrine 1:100,000 and 1:200,000, respectively. Articaine is excreted primarily through urine with 53-57% of the administered dose eliminated in the first 24 hours following submucosal administration. Articainic acid is the primary metabolite in urine. minor metabolite, articainic acid glucuronide, is also excreted in urine. Articaine constitutes only 2% of the total dose excreted in urine.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of ARTICADENT. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Persistent paresthesias of the lips, tongue, and oral tissues have been reported with use of articaine hydrochloride, with slow, incomplete, or no recovery. These postmarketing events have been reported chiefly following nerve blocks in the mandible and have involved the trigeminal nerve and its branches.Hypoesthesia has been reported with use of articaine, especially in pediatric age groups, which is usually reversible. Prolonged numbness can result in soft tissue injuries such as that of the lips and tongue in these age groups.Ischemic injury and necrosis have been described following use of articaine with epinephrine and have been postulated to be due to vascular spasm of terminal arterial branches.Paralysis of ocular muscles has been reported, especially after posterior, superior alveolar injections of articaine during dental anesthesia. Symptoms include diplopia, mydriasis, ptosis, and difficulty in abduction of the affected eye. These symptoms have been described as developing immediately after injection of the anesthetic solution and persisting one minute to several hours, with generally complete recovery.

PREGNANCY SECTION.

8.1 Pregnancy. Teratogenic Effects Pregnancy Category C.There are no adequate and well-controlled studies in pregnant women with ARTICADENT. Articaine hydrochloride and epinephrine (1:100,000) has been shown to increase fetal deaths and skeletal variations in rabbits when given in doses approximately times the maximum recommended human dose (MRHD). ARTICADENT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.In embryo-fetal toxicity studies in rabbits, 80 mg/kg, subcutaneously (approximately times the MRHD based on body surface area) caused fetal death and increased fetal skeletal variations, but these effects may be attributable to severe maternal toxicity, including seizures, observed at this dose. In contrast, no embryo-fetal toxicities were observed when articaine and epinephrine (1:100,000) was administered subcutaneously throughout organogenesis at doses up to 40 mg/kg in rabbits and 80 mg/kg in rats (approximately times the MRHD based on body surface area).In pre- and postnatal developmental studies subcutaneous administration of articaine hydrochloride to pregnant rats throughout gestation and lactation, at dose of 80 mg/kg (approximately times the MRHD based on body surface area) increased the number of stillbirths and adversely affected passive avoidance, measure of learning, in pups. This dose also produced severe maternal toxicity in some animals. dose of 40 mg/kg (approximately equal to the MRHD on mg/m2 basis) did not produce these effects. similar study using articaine and epinephrine (1:100,000) rather than articaine hydrochloride alone produced maternal toxicity, but no effects on offspring.

SPL UNCLASSIFIED SECTION.

2.1 Important Dosage Information. Table summarizes the recommended dosages of ARTICADENT administered by intraoral submucosal infiltration or nerve block for various types of anesthetic dental procedures in healthy adults and pediatric patients.Table 1: Recommended Dosages for Both StrengthsProcedureARTICADENT InjectionVolume (mL)Total dose of articaine HCl (mg)Infiltration0.5 mL to 2.5 mL20 mg to 100 mgNerve block0.5 mL to 3.4 mL20 mg to 136 mgOral surgery1 mL to 5.1 mL40 mg to 204 mgThe recommended dosages of ARTICADENT in healthy adults serve only as guide to the amount of anesthetic required for most routine dental procedures. The dosages to be used in adults depend on several factors such as type and extent of surgical procedure, depth of anesthesia, degree of muscular relaxation, and condition of the patient. In all cases, administer the lowest dosage that will produce the desired result.The dosages of ARTICADENT to be used in pediatric patients aged to 16 years old are determined by the age and weight of the patient and the type of dental procedure. For most routine dental procedures, ARTICADENT containing epinephrine 1:200,000 is preferred. However, when more pronounced hemostasis or improved visualization of the surgical field are required, ARTICADENT containing epinephrine 1:100,000 may be used.The onset of anesthesia and the duration of anesthesia are proportional to the dosage of the local anesthetic used. Exercise caution when employing large volumes because the incidence of adverse reactions may be dose-related.

TERATOGENIC EFFECTS SECTION.

Teratogenic Effects Pregnancy Category C.There are no adequate and well-controlled studies in pregnant women with ARTICADENT. Articaine hydrochloride and epinephrine (1:100,000) has been shown to increase fetal deaths and skeletal variations in rabbits when given in doses approximately times the maximum recommended human dose (MRHD). ARTICADENT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.In embryo-fetal toxicity studies in rabbits, 80 mg/kg, subcutaneously (approximately times the MRHD based on body surface area) caused fetal death and increased fetal skeletal variations, but these effects may be attributable to severe maternal toxicity, including seizures, observed at this dose. In contrast, no embryo-fetal toxicities were observed when articaine and epinephrine (1:100,000) was administered subcutaneously throughout organogenesis at doses up to 40 mg/kg in rabbits and 80 mg/kg in rats (approximately times the MRHD based on body surface area).In pre- and postnatal developmental studies subcutaneous administration of articaine hydrochloride to pregnant rats throughout gestation and lactation, at dose of 80 mg/kg (approximately times the MRHD based on body surface area) increased the number of stillbirths and adversely affected passive avoidance, measure of learning, in pups. This dose also produced severe maternal toxicity in some animals. dose of 40 mg/kg (approximately equal to the MRHD on mg/m2 basis) did not produce these effects. similar study using articaine and epinephrine (1:100,000) rather than articaine hydrochloride alone produced maternal toxicity, but no effects on offspring.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal studies, may cause fetal harm. (8.1)Nursing Mothers: Exercise caution when administering to nursing woman. (8.3)Pediatric Use: Safety and effectiveness in pediatric patients below the age of years have not been established. (8.4). 8.1 Pregnancy. Teratogenic Effects Pregnancy Category C.There are no adequate and well-controlled studies in pregnant women with ARTICADENT. Articaine hydrochloride and epinephrine (1:100,000) has been shown to increase fetal deaths and skeletal variations in rabbits when given in doses approximately times the maximum recommended human dose (MRHD). ARTICADENT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.In embryo-fetal toxicity studies in rabbits, 80 mg/kg, subcutaneously (approximately times the MRHD based on body surface area) caused fetal death and increased fetal skeletal variations, but these effects may be attributable to severe maternal toxicity, including seizures, observed at this dose. In contrast, no embryo-fetal toxicities were observed when articaine and epinephrine (1:100,000) was administered subcutaneously throughout organogenesis at doses up to 40 mg/kg in rabbits and 80 mg/kg in rats (approximately times the MRHD based on body surface area).In pre- and postnatal developmental studies subcutaneous administration of articaine hydrochloride to pregnant rats throughout gestation and lactation, at dose of 80 mg/kg (approximately times the MRHD based on body surface area) increased the number of stillbirths and adversely affected passive avoidance, measure of learning, in pups. This dose also produced severe maternal toxicity in some animals. dose of 40 mg/kg (approximately equal to the MRHD on mg/m2 basis) did not produce these effects. similar study using articaine and epinephrine (1:100,000) rather than articaine hydrochloride alone produced maternal toxicity, but no effects on offspring.. 8.3 Nursing Mothers. It is not known whether ARTICADENT is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ARTICADENT is administered to nursing woman. When using ARTICADENT, nursing mothers may choose to pump and discard breast milk for approximately hours (based on plasma half-life) following an injection of ARTICADENT (to minimize infant ingestion) and then resume breastfeeding.. 8.4 Pediatric Use. Safety and effectiveness of ARTICADENT in pediatric patients below the age of years have not been established. Safety of doses greater than mg/kg (0.175 mL/kg) in pediatric patients has not been established.The safety and effectiveness of ARTICADENT for local, infiltrative, or conductive anesthesia in both simple and complex dental procedures have been established in pediatric patients ages to 16 years old. Safety and effectiveness was established in clinical trials with 61 pediatric patients between the ages of and 16 years administered articaine hydrochloride 4% and epinephrine 1:100,000 injections. Fifty-one of these patients received doses from 0.76 mg/kg to 5.65 mg/kg (0.9 to 5.1 mL) for simple dental procedures and 10 patients received doses between 0.37 mg/kg and 7.48 mg/kg (0.7 to 3.9 mL) for complex dental procedures. Approximately 13% of these pediatric patients required additional injections of anesthetic for complete anesthesia. Dosages in pediatric patients should be reduced, commensurate with age, body weight, and physical condition [see Dosage and Administration (2.2)]. 8.5 Geriatric Use. In clinical trials, 54 patients between the ages of 65 and 75 years, and 11 patients 75 years and over received ARTICADENT containing epinephrine 1:100,000. Among all patients between 65 and 75 years, doses from 0.43 mg/kg to 4.76 mg/kg (0.9 to 11.9 mL) were administered to 35 patients for simple procedures and doses from 1.05 mg/kg to 4.27 mg/kg (1.3 to 6.8 mL) were administered to 19 patients for complex procedures. Among the 11 patients >= 75 years old, doses from 0.78 mg/kg to 4.76 mg/kg (1.3 to 11.9 mL) were administered to patients for simple procedures and doses of 1.12 mg/kg to 2.17 mg/kg (1.3 to 5.1 mL) were administered to patients for complex procedures. Approximately 6% of patients between the ages of 65 and 75 years and none of the 11 patients 75 years of age or older required additional injections of anesthetic for complete anesthesia compared with 11% of patients between 17 and 65 years old who required additional injections.No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.. 8.6 Renal and Hepatic Impairment. No studies have been performed with articaine hydrochloride 4% and epinephrine 1:200,000 injection or articaine hydrochloride 4% and epinephrine 1:100,000 injection in patients with renal or hepatic impairment [see Warnings and Precautions (5.2)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Accidental Intravascular Injection: May be associated with convulsions followed by coma and respiratory arrest. Resuscitative equipment, oxygen and other resuscitative drugs should be available. (5.1)Systemic Toxicity: Systemic absorption of ARTICADENT can produce effects on the central nervous and cardiovascular systems. (5.2)Vasoconstrictor Toxicity: Local anesthetic solutions like ARTICADENT that contain vasoconstrictor should be used cautiously, especially in patients with impaired cardiovascular function or vascular disease. (5.3)Methemoglobinemia: Cases of methemoglobinemia have been reported in association with local anesthetic use. (5.4). 5.1 Accidental Intravascular Injection. Accidental intravascular injection of ARTICADENT may be associated with convulsions, followed by central nervous system or cardiorespiratory depression and coma, progressing ultimately to respiratory arrest. Dental practitioners who employ local anesthetic agents including ARTICADENT should be well versed in diagnosis and management of emergencies that may arise from their use. Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use. To avoid intravascular injection, aspiration should be performed before ARTICADENT is injected. The needle must be repositioned until no return of blood can be elicited by aspiration. Note, however, that the absence of blood in the syringe does not guarantee that intravascular injection has been avoided.Small doses of local anesthetics injected in dental blocks may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. Confusion, convulsions, respiratory depression or respiratory arrest, and cardiovascular stimulation or depression have been reported. These reactions may be due to intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. Patients receiving these blocks should be observed constantly. Resuscitative equipment and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded [see Dosage and Administration (2.1)].. 5.2 Systemic Toxicity. This includes toxicity arising from accidental intravascular injection of ARTICADENT discussed in Section 5.1, as well as that related to higher systemic concentrations of local anesthetics or epinephrine [see Warnings and Precautions (5.3)]. Systemic absorption of local anesthetics including ARTICADENT can produce effects on the central nervous and cardiovascular systems.At blood concentrations achieved with therapeutic doses of ARTICADENT, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations of ARTICADENT can depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias, and cardiac arrest, possibly resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilatation occurs, leading to decreased cardiac output and arterial blood pressure. ARTICADENT should also be used with caution in patients with heart block as well as those with impaired cardiovascular function since they may be less able to compensate for functional changes associated with the prolongation of A-V conduction produced by these drugs. Restlessness, anxiety, tinnitus, dizziness, blurred vision, tremors, depression, or drowsiness may be early warning signs of central nervous system toxicity. Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patients state of consciousness should be performed after each local anesthetic injection of ARTICADENT. Repeated doses of ARTICADENT may cause significant increases in blood levels because of possible accumulation of the drug or its metabolites.The lowest dosage that results in effective anesthesia should be used to decrease the risk of high plasma levels and serious adverse effects. Tolerance to elevated blood levels varies with the status of the patient. Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use. Precautions for epinephrine administration, discussed in Section 5.3, should be observed.Debilitated patients, elderly patients, acutely ill patients, and pediatric patients should be given reduced doses commensurate with their age and physical condition [see Dosage and Administration (2.1, 2.3)]. No studies have been performed in patients with liver impairment, and caution should be used in patients with severe hepatic disease.. 5.3 Vasoconstrictor Toxicity. ARTICADENT contains epinephrine, vasoconstrictor that can cause local or systemic toxicity and should be used cautiously. Local toxicity may include ischemic injury or necrosis, which may be related to vascular spasm. ARTICADENT should be used with caution in patients during and following the administration of potent general anesthetic agents, since cardiac arrhythmias may occur under such conditions. Patients with peripheral vascular disease and those with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response.The American Heart Association has made the following recommendation regarding the use of local anesthetics with vasoconstrictors in patients with ischemic heart disease: Vasoconstrictor agents should be used in local anesthesia solutions during dental practice only when it is clear that the procedure will be shortened or the analgesia rendered more profound. When vasoconstrictor is indicated, extreme care should be taken to avoid intravascular injection. The minimum possible amount of vasoconstrictor should be used. (Kaplan, 1986). It is essential to aspirate before any injection to avoid administration of the drug into the blood stream.. 5.4 Methemoglobinemia. Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended.Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure and are characterized by cyanotic skin discoloration, and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue ARTICADENT and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.. 5.5 Anaphylaxis and Allergic-Type Reactions. ARTICADENT contains sodium metabisulfite, sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.